Novel 4-hydroxy-3-pyridine-carboxamides useful for treating inflammation and rheumatism

ABSTRACT

Novel pyridines of the formula ##STR1## wherein R is selected from the group consisting of (a) phenyl optionally substituted with at least one member of the group consisting of hydroxy, alkyl and alkoxy of 1 to 5 carbon atoms, halogen, --CF 3  and --NO 2  and (b) a 5 to 6 member hetercyclic optionally substituted with alkyl of 1 to 5 carbon atoms, R 1  and R 2  are individually selected from the group consisting of (a) alkyl of 1 to 5 carbon atoms, (b) 5 to 6 member heterocyclic optionally substituted with alkyl of 1 to 5 carbon atoms and (c) phenyl and naphthyl optionally substituted with at least one member of the group consisting of hydroxy, alkyl and alkoxy of 1 to 5 carbon atoms, halogen, --NO 3  and --CF 3 , R 3  is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, --(CF 2 ) n  --CF 3  and ##STR2## n is an integer from 0 to 4 and Alk is alkyl of 1 to 5 carbon atoms and their non-toxic, pharmaceutically acceptable salts with acids and bases having anti-inflammatory and anti-rheumatic properties.

STATE OF THE ART

Related pyridines are described in British Patent No. 2,171,097; U.S.Pat. No. 4,299,381 and French Patent No. 2,537.140.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and their non-toxic, pharmaceutically acceptable salts and aprocess for their preparation.

It is another object of the invention to provide novel anti-inflammatoryand anti-rheumatic compositions and a novel method of combattinginflammation and rheumatic conditions in warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of pyridines of the formula ##STR3## wherein R is selectedfrom the group consisting of (a) phenyl optionally substituted with atleast one member of the group consisting of hydroxy, alkyl and alkoxy of1 to 5 carbon atoms, halogen, --CF₃ and --NO₂ and (b) a 5 to 6 memberheterocyclic optionally substituted with alkyl of 1 to 5 carbon atoms,R₁ and R₂ are individually selected from the group consisting of (a)alkyl of 1 to 5 carbon atoms, (b) 5 to 6 member heterocyclic optionallysubstituted with alkyl of 1 to 5 carbon atoms and (a) phenyl andnaphthyl optionally substituted with at least one member of the groupconsisting of hydroxy, alkyl and alkoxy of 1 to 5 carbon atoms, halogen,--NO₃ and --CF₃, R₃ is selected from the group consisting of hydrogen,alkyl of 1 to 5 carbon atoms, --(CF₂)_(n) --CF₃ and ##STR4## n is aninteger from 0 to 4 and Alk is alkyl of 1 to 5 carbon atoms and theirnon-toxic, pharmaceutically acceptable salts with acids and bases.

When R₁, R₂ and R₃ is alkyl, they are preferably methyl or ethyl, butthey may also be n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl orn-pentyl.

When R is heterocyclic of 5 or 6 links, it is preferably thiazolyl,4,5-dihydrothiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl,pyrimidyl or tetrazolyl. When these heterocyclic radicals aresubstituted by alkyl, it is preferably methyl or ethyl.

When R is substituted phenyl, and when R₁ and R₂ are substituted phenylor naphthyl, it is preferably a substituent selected from the groupconsisting of methyl, ethyl, ethoxy and trifluoromethyl, halogen such aschlorine, fluorine, bromine or iodine and preferably chlorine.

When R₃ is --(CF₂)_(n) CF₃, n is preferably 0, 1 or 2. When R₁ and R₂are a heterocyclic, it is preferably pyridinyl or thienyl. When thisradical is substituted with alkyl, it is preferably methyl or ethyl.

The addition salts with mineral or organic acids can be, for example,the salts formed with the following acids: hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, aceticacid, propionic acid, formic acid, benzoic acid, maleic acid, fumaricacid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylicacid, aspartic acid, alkanesulfonic acids such as methanesulfonic acidand arylsulfonic acids such as benzene sulfonic acid.

Among the addition salts with bases, there may be cited those formedwith the alkali metals such as sodium, potassium and amines, forexample, trimethylamine or dimethylamine.

Among the preferred compounds of formula I are those wherein R isthiazolyl, 4,5-dihydrothiazolyl, phenyl or pyridinyl, those wherein R₃is --CF₃ or ##STR5## and Alk is alkyl of 1 to 5 carbon atoms, thosewherein R₁ and R₂ both are phenyl optionally substituted with at leastone member of the group consisting of methyl, ethyl, methoxy, ethoxy,halogen and --CF₃ and those wherein one of R₁ and R₂ is methyl and theother is phenyl optionally substituted with at least one member of thegroup consisting of methyl, ethyl, methoxy, ethoxy, halogen and --CF₃and their non-toxic, pharmaceutically acceptable salts with acids andbases.

Examples of specific preferred compounds of the invention are:

4-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,

5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,

5,6-bis-(4-chlorophenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,

5,6-diphenyl-4-hydroxy-2-(1-hydroxypropyl)-4-(2-thiazolyl)-3-pyridinecarboxamide

and their non-toxic, pharmaceutically acceptable salts with acids andbases.

The novel process of the invention for the preparation of the compoundsof formula I comprises reacting a compound of the formula ##STR6##wherein R₁ and R₂ have the above definitions with an acid of the formula

    R.sub.3 --COOH                                             IV

or a functional derivative thereof wherein R₃ has the above definitionto obtain a compound of the formula ##STR7## reacting the latter with achlorinating agent to obtain a compound of the formula ##STR8## reactingthe latter with an alkyl malonate of the formula Alk₁ OOC--CH₂ --COOAlk₁wherein Alk₁ is alkyl of 1 to 5 carbon atoms in the presence of a strongbase to obtain a compound of the formula ##STR9## cyclizing the latterto obtain a compound of the formula ##STR10## reacting the latter withan amine of the formula NH₂ R wherein R has the above definition toobtain the corresponding compound of formula I.

A modification of the process to form the compounds of formula Icomprises reacting a compound of the formula ##STR11## wherein R₁ and R₂have the above definition and Alk₂ is alkyl of 1 to 5 carbon atoms withan acid of formula IV or a functional derivative thereof to obtain acompound of the formula ##STR12## subjecting the latter to hydrolysis toform the corresponding free acid and cyclizing the latter to obtain acompound of the formula ##STR13## subjecting the latter to an anion ofan alkyl acetate of the formula CH₃ --COOAlk₃, Alk₃ being alkyl of 1 to5 carbon atoms to obtain a compound of the formula ##STR14## andcyclizing the latter to obtain a compound of formula VIII which is thenreacted with an amine of the formula NH₂ --R to obtain the compound offormula I.

A variation of the process comprises reacting a compound of formula IXwith a compound of the formula ##STR15## wherein R has the abovedefinition to obtain a compound of the formula ##STR16## and cyclizingthe latter to obtain the corresponding compound of formula I.

In a preferred mode of the process of the invention, the acid of formulaIV is used in the form of its acid anhydride or acid chloride and thereaction with the amine of formula III is effected in the presence of abase such as triethylamine. When R₃ is ##STR17## in formula I, the acidof formula IV has the hydroxyl protected such as with an alkyl of 1 to 4carbon atoms, halogen or aryl which is removed after reaction with theamine of the formula NH₂ --R, for example by reaction withtrimethylsilane iodide or boron tribromide preferably.

The chlorinating agent reacted with the compound of formula V ispreferably phosphorus pentachloride or a mixture of triphenyl phosphineand carbon tetrachloride. The alkyl malonate is preferably diethylmalonate and the reaction is effected in the presence of sodium hydride.

The cyclization of the compounds of formula VII is preferably effectedby heating at 150° to 250° C., for example. The hydrolysis of thecompound of formula X may be effected with hydrochloric acid or sodiumhydroxide and the corresponding acid may be cyclized in the presence ofacetic anhydride or trifluoroacetic anhydride to form the compound offormula XI.

The compound of formula XI may be reacted with the zinc derivative ofethyl bromoacetate in the presence of methylal to obtain the compound offormula XII. The condensation of the compound of formula VIII with theamine of the formula NH₂ R is preferably effected in the presence of abase such as sodium hydride or a trialkylaluminium such astrimethylaluminium or triisobutylauminium.

The reaction of the compounds of formulae XI and XIV is preferablyeffected in the presence of an organo lithium or lithium amide such asin the presence of n-butyllithium or lithium diisopropylamide at lowtemperatures on the order of -70° C. The cyclization of compounds offormulae XII or XV is effected in the presence of an alkaline agent suchas sodium hydride or an alkali metal carbonate such as sodium carbonateor potassium carbonate or potassium tert.-butylate or an amine such as4-dimethylaminopyridine, piperidine or triethylamine.

The novel anti-inflammatory and anti-rheumatic compositions of theinvention are comprised of an anti-inflammatorily and anti-rheumaticallyeffective amount of at least one compound of formula I and itsnon-toxic, pharmaceutically acceptable addition salts with acids orbases and an inert pharmaceutical carrier or excipient. The compositionsmay be in the form of tablets, dragees, capsules, granules,suppositories, ointments, creams, gels, injectable solutions orsuspensions and aerosol preparations.

The compositions are useful for the treatment of chronic inflammationand certain types of auto-immune diseases and have a peripheralanalgesic activity. They are useful for the treatment of degenerativeinflammatory diseases such as osteoarthroses, the various collagenoses,(tendinites, etc. . . . ) rheumatic diseases (rheumatoid polyarthritis,ankylosing spondyl-arthritis) as well as in the treatment of otherdisease of an auto-immune nature such as disseminated erythematouslupus, glomerulo-nephritis, disseminated sclerosis as well as in thetreatment of psoriasis. They also may be used in the treatment ofmuscular, articular or nervous pains, dental pains, migraines, andshingles.

Examples of suitable excipients are talc, gum arabic, lactose,starch,magnesium stearte, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,the various wetting dispersing or emulsifying agents and preservatives.

Among the preferred compositions are those wherein the active ingredientis selected from the group consisting of

4-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,

5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,

5,6-bis-(4-chlorophenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl-3-pyridinecarboxamide,

5,6-diphenyl-4-hydroxy-2-(1-hydroxypropyl)-4-(2-thiazolyl)-3-pyridinecarboxamide,

and their addition salts with pharmaceutically acceptable acids andbases.

The novel method of the invention for treating inflammation andrheumatism in warm-blooded animals, including humans, comprisesadministering to warm-blooded animals an anti-inflammatorily andanti-rheumatically effective amount of at least one compound of formulaI and their non-toxic, pharmaceutically acceptable addition salts withacids and bases. The compounds may be administered orally, rectally,parenterally or topically to the skin and mucosa. The usual effectivedaily dose is 0.25 to 25 mg/kg depending upon the condition treated, thespecific compound and the method of administration.

The starting materials of formula III may be prepared by reacting acompound of the formula ##STR18## (Tetrahedron Letters 1971 (51) p.4897) with ammonia in the presence of a titanium salt such as titaniumtetrachloride. The starting materials of formula IX are prepared by theprocess of European Patent No. 102,318.

The novel intermediates of the invention are the compounds of formulaIII wherein R₁ and R₂ are phenyl substituted by methoxy or chlorine, thecompounds of formula V when R₃ is other than methyl and R₁ and R₂ areboth phenyl, the compounds of formulae XII and XV, and the compounds offormulae VI, VII, VIII, X and the acids of the esters of formulae X andXI except when R₃ is methyl.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 14-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-trifluoromethyl-3-pyridinecarboxamide STEP A: Ethyl 3-amino-2-methyl-3-phenyl-2-propenoate

Under vigorous agitation, 73.2 g of powdered electrolytic zinc wererefluxed in 1.2 liter of anhydrous tetrahydrofuran and 10 ml of ethyl2-bromopropionate were added together with a crystal of sublimed iodine.The reaction started and then, away from reflux, 40.8 ml of benzonitrilewere added and the mixture was refluxed which was maintained by the slowaddition of 58 ml of ethyl 2-bromopropionate. After cooling, the mixturewas poured into 1.5 liters of water containing 200 g of ammoniumchloride and extraction was done with ether. The extracts were washedwith water, dried, and concentrated under reduced pressure. The residuewas taken up with ether and the insoluble matter was filtered off. Thefiltrate was concentrated under reduced pressure to obtain 76 g of anunstable product which was used rapidly for the next step.

STEP B: 2-methyl-3-phenyl-3-[(trifluoroacetyl)-amino]-2-propenoic acid

56 ml of trifluoroacetic anhydride were added to 53 g of the product ofStep A in 200 ml of pyridine while the temperature was maintainedbetween 20° and 24° C. The solution was poured into a liter of icedwater and 110 ml of concentrated hydrochloric acid (pH=1) were addedslowly. Extraction was done with ether and the organic phase was washedwith water, dried and concentrated to dryness under reduced pressure.The oily residue was added to 400 ml of a saturated aqueous solution ofsodium bicarbonate, followed by extraction with ether. The etherealextracts were washed with water, and the combined aqueous phases wereacidified to a pH of 1 with concentrated hydrochloric acid. Extractionwas done with ether and the organic phase was washed with water, driedand concentrated to dryness under reduced pressure to obtain 39.3 g ofthe expected product melting at 140° C.

STEP C: 5-methyl-4-phenyl-2-(trifluoromethyl)-6H-1,3-oxazine-6-one

39.3 g of the product of Step B were refluxed in 80 ml of aceticanhydride and maintained at this temperature for 30 minutes and thenallowed to cool. The acetic anhydride was expelled under reducedpressure and iced water was added to the residue. The precipitateobtained was separated, washed abundantly with water and then dissolvedin ether. The organic solution was dried and concentrated to drynessunder reduced pressure to obtain 34 g of the expected product melting at70° C.

STEP D:4-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-trifluoromethyl-3-pyridinecarboxamide

12.25 g of 2-acetylamino thiazole were cooled to 0° C. in 370 ml oftetrahydrofuran and then 122 ml of a 1.4M solution of n-butyllithium inhexane were added. The mixture was cooled to -70° C. to -75° C., andheld at this temperature while adding a solution of 11 g of5-methyl-4-phenyl-2-(trifluoromethyl)-6H-1,3-oxazine-6-one in 100 ml oftetrahydrofuran. The solution at -70° C. was poured into 700 ml of waterand 150 ml of 2N hydrochloric acid. Extraction was done with ether andthe extracts were washed with N hydrochloric acid, then with water,dried, and concentrated to dryness under reduced pressure to obtain 24 gof intermediate product. The latter was stirred with 100 ml oftetrahydrofuran and 5.25 g of 4-dimethylaminopyridine for 1 hour atambient temperature and 30 minutes at reflux. After cooling, thereaction mixture was poured into 300 ml of water acidified to pH 1 withhydrochloric acid. After extracting with ethyl acetate, washing, dryingand concentrating under reduced pressure, 23 g of product were obtainedwhich was taken up in ether. 3.5 g of crystallized product melting at242° C., corresponding to the5-methyl-4-phenyl-2-(trifluoromethyl)-2-(thiazolylamino-carbonylmethyl)-6H-1,3-oxazin-6-oneseparated. A second product slowly crystallized from the ethereal motherliquors and this was separated. The crystals formed were washed withether to obtain 5.5 g of the expected product. After crystallizing fromacetonitrile, 2.8 g of product melted at 256° C.

Analysis: C₁₇ H₁₂ N₃ O₂ F₃ S; molecular weight=379.373. Calculated: % C53.82, % H 3.19, % N 11.08, % F 15.02, % S 8.45. Found: % C 53.6, % H3.1, % N 11.1, % F 14.8, % S 8.6.

EXAMPLE 2 2,5-dimethyl-4-hydroxy-6-phenyl-N-(2-thiazolyl)-3-pyridinecarboxamide STEP A: Ethyl 3-(acetylamino)-2-methyl-3-phenyl-2-propenoate

76 g of ethyl 3-amino-2-methyl-3-phenyl-2-propenoate were maintained at15° C. in 600 ml of tetrahydrofuran and 32.3 ml of pyridine while adding28.44 ml of acetyl chloride in 100 ml of tetrahydrofuran. The mixturewas refluxed for 1 hour, then cooled and poured into a liter of wateracidified to pH 1 with 2N hydrochloric acid. After extracting withether, washing with water, with a saturated solution of sodiumbicarbonate and then with water, drying and concentrating to drynessunder reduced pressure, 80 g of the expected product were obtained.

STEP B: 3-acetylamino-2-methyl-3-phenyl-2-propenoic acid

80 g of the product of Step A were stirred for 5 hours in 400 ml ofisopropanol and 48.5 ml of sodium hydroxide and the solution was pouredinto a liter of water taken to pH 1 with concentrated hydrochloric acid.The precipitate was separated, washed with water and dried under reducedpressure to obtain 42 g of the expected product melting at 190° C.

STEP C: 2,5-dimethyl-4-phenyl-6H-1,3-oxazin-6-one

Using the procedure of Step C of Example 1, 10 g of the product of StepB was maintained for 2 hours at reflux and the residue was triturated inn-hexane, then separated, washed and dried under reduced pressure toobtain 7.8 g of the expected product which was not very stable in theair and melted at 68° C.

STEP D: 2,5-dimethyl-4-hydroxy-6-phenyl-N-(2-thiazolyl)-3-pyridinecarboxamide

Using the procedure of Step D of Example 1, 3.3 g of the product of StepC were reacted. Extraction was done with ethyl acetate and the extractswere concentrated under reduced pressure. The residue crystallizedslowly and the crystals were triturated in ethyl acetate and separatedto obtain 4.5 g of intermediate product which was dissolved in 100 ml oftetrahydrofuran and filtered. The filtrate was concentrated to about 50ml and precipitated with ether to obtain 2.75 g of impure product. 2.3 gof the latter were taken up in 46 ml of tetrahydrofuran and 1 g ofpotassium tert-butylate and the mixture was taken progressively toreflux and kept there for 90 minutes. After cooling, the mixture waspoured into 100 ml of water with 5 ml of 2N hydrochloric acid, andextracted with a 50-50 mixture of ethyl acetate and tetrahydrofuran,followed by washing with water, drying and concentrating under reducedpressure. The residue was triturated in ether and 1.6 g of productseparated which was crystallized successively from ethyl acetate and 96%ethanol to obtain 1.2 g of product melting at 266° C. 1.16 g of thelatter was purified by preparing the hydrochloride with 1 ml of a 5.7Nsolution of hydrochloric acid in ethanol and 1 g of the isolatedhydrochloride was stirred in 30 ml of water for 15 minutes at ambienttemperature. The precipitate was separated, washed abundantly withwater, and while still humid was dissolved again in 150 ml oftetrahydrofuran. The solution was dried and concentrated to drynessunder reduced pressure. The residue was triturated in ether, separated,washed with ether and dried to obtain 735 mg of the expected productmelting at 270° C.

Analysis: C₁₇ H₁₅ O₂ N₃ S; molecular weight=325.393. Calculated: % C62.75, % H 4.65, % N 12.91, % S 9.85. Found: % C 62.9, % H 4.7, % N12.7, % S 9.6.

EXAMPLE 35,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-trifluoromethyl-3-pyridinecarboxamide STEP A: Ethyl 3-amino-(2,3-diphenyl)-2-propenoate

Using the procedure of Step A of Example 1, 59 ml of ethyl α-bromophenylacetate in toluene were reacted and the ethereal extracts were washedwith water, dried and concentrated to dryness to obtain an oily residueof about 70 g which were used as is for the following step.

STEP B: (2,3-diphenyl-3-(trifluoroacetyl)-amino-2-propenoic acid

Using the procedure of Step B of Example 1, 70 g of the product of StepA were reacted to obtain 36 g of the expected product melting at 175° C.

STEP C: 2-trifluoromethyl-4,5-diphenyl-6H-1,3-oxazin-6-one

Using the procedure of Step C of Example 1, 10 g of the product of StepB were reacted and the residue was triturated in n-hexane, iced,separated, washed and dried under reduced pressure to obtain 7.4 g ofthe expected product melting at 118° C.

STEP D: Ethyl 5,6-diphenyl-4-hydroxy-2-(trifluoromethyl)-3-pyridinecarboxylate

Under stirring, 5.88 g of zinc and 60 ml of methylal were mixed togetherand 1 ml of ethyl bromoacetate and a crystal of iodine were added. Themixture was refluxed and 9.5 g of the product of Step C and 80 ml ofmethylal were added. Then, while maintaining reflux, 7.3 ml of ethylbromoacetate and 60 ml of methylal were added. Reflux was maintained for44 hours and after cooling, the mixture was poured into 300 ml of watercontaining 50 g of ammonium chloride, then extracted with ether. Theorganic phase was washed with water, dried and concentrated underreduced pressure to obtain 12 g of product. The latter was dissolved in200 ml of ether, 50 ml of water and 70 ml of N sodium hydroxide. Afterdecanting, the ethereal phase was washed with water and the combinedaqueous phases were acidified to pH 1 with concentrated hydrochloricacid, then extracted with ether, washed with water, dried andconcentrated under reduced pressure. The residue was chromatographed onsilica to obtain 3.2 g of the expected product melting at 130° C.

STEP E:5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-trifluoromethyl-3-pyridine-carboxamide

3.22 g of 2-aminothiazole were cooled to +2° C. in 80 ml of methylenechloride, and while maintaining the temperature between +2° and +5° C.17.9 ml of triisobutyl aluminium in toluene (0.9M) were added andstirred for 20 minutes. 2.5 g of the product of Step D were thenintroduced all at once into the mixture and the temperature was broughtup progressively to reflux and kept there for 24 hours then lowered tothe ambient. The mixture was concentrated to dryness under reducedpressure and 50 ml of water and 50 ml of 2N hydrochloric acid were addedto the residue. The mixture was triturated and the precipitate wasseparated and washed abundantly with water. While still humid, thelatter was dissolved in tetrahydrofuran and the solution was dried andconcentrated under reduced pressure. The 2.6 g of residue weretriturated in ether, separated and dried to obtain 2.05 g of productmelting at 256° C. After crystallizing from acetonitrile, 1.48 g of theexpected product melted at 256° C.

Analysis: C₂₂ H₁₄ N₃ F₃ O₂ S; molecular weight=441.44. Calculated: % C59,86, % H 3.20, % N 9.52, % F 12.91, % S 7.26. Found: % C 59.8, % H3.1, % N 9.4, % F 12.7, % S 7.3.

EXAMPLE 4 4-hydroxy-2-trifluoromethyl-N-5,6-triphenyl-3-pyridinecarboxamide STEP A: N-(1,2-diphenylethenyl)-trifluoroacetamide

9.8 g of 1,2-diphenylethanone were cooled to 0° C. to 5° C. in 250 ml ofa toluene-ether (1-2) mixture and after stirring, ammonia was bubbled inand the temperature was maintained, followed by adding over 30 minutes,6.85 ml of titanium tetrachloride in 30 ml of an ether-toluene (1-1)mixture. The temperature was allowed to return to ambient and thebubbling in was regulated to maintain it at 20° to 25° C. After 6 hours,the bubbling in was stopped and the mixture was stirred for 16 hours. Itwas then filtered and washed with ether and the filtrate wasconcentrated to dryness under reduced pressure to obtain 7.6 g of1-amino-1,2-(diphenyl)-ethenyl.

26 g of 1-amino-1,2-(diphenyl)-ethenyl was cooled to 0° C. with 130 mlof tetrahydrofuran and 22 ml of triethylamine and 21.67 ml oftrifluoroacetic anhydride in 60 ml of tetrahydrofuran were added. Themixture was stirred for 30 minutes while allowing the temperature toreturn to ambient and was then poured into 500 ml of water, andextracted with ether. The organic phase was washed with water, dried andconcentrated to dryness under reduced pressure. The residue wastriturated in 100 ml of a (10-90) mixture of isopropyl ether andpetroleum ether (b.p. 40° to -70° C.), then separated, washed and driedto obtain 13.8 g of the expected product melting at 148° to 150° C.

STEP B: N-[1,2-diphenylethenyl]-trifluoro-ethanimidoyl chloride

18.4 g of the product of Step A were refluxed for 4 hours in 320 ml ofmethylene chloride, 18.22 g of triphenylphosphine and 6.7 ml of carbontetrachloride. 9.11 g of triphenylphosphine in 3.35 ml of carbontetrachloride were added without reflux and after heating for a furtherone hour at reflux, the mixture stood for 16 hours at ambienttemperature. The solvents were expelled under reduced pressure and theresidue was triturated in a 1-1 mixture of ether and methylene chloride,then separated. The filtrate was concentrated under reduced pressure andthe residue was chromatographed on silica and eluted with methylenechloride to obtain 18.7 g of the expected product.

STEP C: Ethyl[1-[(1,2-diphenylethenyl)-imino-2,2,2-trifluoroethylpropane dioate]

To 1.4 g of 50% sodium hydride in 15 ml of dimethylformamide, there wereadded 4.6 ml of ethyl malonate in 15 ml of dimethylformamide while at atemperature between 10° C. and 15° C. and the mixture was stirred for afurther 80 minutes at +15° C. 4.5 g of the product of Step B were addedin 15 ml of dimethylformamide, followed by stirring for 1 hour atambient temperature. The mixture was poured into 90 ml of wateracidified to pH 1 with hydrochloric acid and extracted with ether. Theextracts were washed with water, dried and concentrated under reducedpressure to obtain 10 g of the expected product.

STEP D: Ethyl 5,6-diphenyl-4-hydroxy-2-trifluoromethyl-3-pyridinecarboxylate

10 g of the product of Step C were stirred vigorously and takenprogressively at 220° C. After cooling, the crystals formed weretriturated in hexane, iced, separated, washed with hexane, and driedunder reduced pressure to obtain 5.2 g of product melting at 130° C.

STEP E: 4-hydroxy-2-trifluoromethyl-N-5,6-triphenyl-3-pyridinecarboxamide

5.03 g of the product of Step D were stirred in 60 ml of toluene and3.63 g of aniline and 1.872 g of a 50% dispersion of sodium hydride inoil were added and the mixture was refluxed for 4 hours. At ambienttemperature, the mixture was poured into water acidified to pH 1 byhydrochloric acid, then extracted with ether, washed with water, driedand concentrated under reduced pressure to obtain 6 g of residue. Thelatter was chromatographed on silica and eluted with a 5-95 mixture ofethyl acetate and methylene chloride to obtain 4 g of product which wascrystallized from a 1-1 mixture of ether and hexane to obtain 3.76 g ofthe expected product melting at 172° C.

Analysis: C₂₅ H₁₇ N₂ O₂ F₃ ; molecular weight=434.426. Calculated: % C69.12, % H 3.94, % N 6.45, % F 13.12. Found: % C 69.3, % H 3.9, % N 6.4,% F 13.4.

EXAMPLE 55,6-diphenyl-4-hydroxy-N-(2-pyridinyl)-2-(trifluoromethyl)-3-pyridinecarboxamide

7.05 g of 2-amino-pyridine in 200 ml of methylene chloride were stirredat 10° to 15° C. and 34 ml of tri-isobutylaminium at 1.1M/l in toluenewere added. Stirring was maintained for 30 minutes at 15° C. and then5.8 g of the product of Step D of Example 4 were added all at once andthe mixture was refluxed for 24 hours. The residue was poured into 100ml of water and 75 ml of 2N hydrochloric acid and stirred for 30minutes. After separating, the precipitate was washed abundantly withwater and dissolved while still humid in tetrahydrofuran. The solutionwas dried and concentrated to dryness and the residue was triturated inether and dried under reduced pressure to obtain 5.5 g of product whichwas crystallized from ethyl acetate to obtain 3.66 g of the expectedproduct melting at 208° to 210° C.

Analysis: C₂₄ H₁₆ N₃ O₂ F₃ ; molecular weight=435.415. Calculated: % C66.20, % H 3.70, % N 9.65, % F 13.09. Found: % C 66.0, % H 3.6, % N 9.8,% F 12.9.

EXAMPLE 65,6-bis-(4-methoxyphenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide

Using the procedure of Step E of Example 3, 6.7 g of ethyl5,6-bis-(4-methoxy-phenyl 4-hydroxy)-2-trifluoromethyl-3-pyridinecarboxylate prepared like the product of Step D of Example 4, startingwith 1,2-bis-(methoxyphenyl) ethanone were reacted to obtain 5 g of theexpected product which after crystallizing from ethyl acetate melted at230° C.

Analysis: C₂₄ H₁₈ N₃ O₄ F₃ S; molecular weight=501.493. Calculated: % C57.48, % H 3.62, % N 8.38, % F 11.37, % S 6.39. Found: % C 57.7, % H3.6, % N 8.4, % F 11.04, % S 6.4.

EXAMPLE 75,6-diphenyl-4-hydroxy-N-(4,5-dihydro-2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide

Using the procedure of Step E of Example 3, 5.1 g of 2-amino thiazolinewere reacted and the precipitate obtained in suspension in acidifiedwater was extracted with a 6-4 mixture of ethyl acetate andtetrahydrofuran. The organic phase was washed with water, dried andconcentrated to dryness under reduced pressure. The residue wastriturated with ether, separated and dried under reduced pressure toobtain 3 g of crude product which after crystallizing from acetonitrileyielded 2.5 g of the expected product melting at 280° C.

Analysis: C₂₂ H₁₆ N₃ O₂ F₃ S; molecular weight=443.456. Calculated: % C59.59, % H 3.64, % N 9.47, % F 12.85, % S 7.23. Found: % C 59.6, % H3.5, % N 9.7, % F 12.6, % S 7.3.

EXAMPLE 85,6-bis-(4-chlorophenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-carboxamide-3-pyridine

Using the procedure of Step E of Example 3, ethyl5,6-bis-(4-chlorophenyl)-4-hydroxy-2-trifluoromethyl-3-pyridinecarboxylate was reacted to obtain the expected product melting at 206°to 208° C.

EXAMPLE 94-hydroxy-5-phenyl-N-(2-thiazolyl)-6-(2-thienyl)-2-trifluoromethyl-3-pyridinecarboxamide. STEP A:N-[2-phenyl-1-(2-thienyl)-ethenyl]-2,2,2-trifluoroacetamide

Using the procedure of Step A of Example 4, 20.2 g of2-phenyl-1-(2-thienyl) ethanone and 17.38 ml of methylamine were reactedto obtain 8.1 g of the expected product melting at 158° C.

STEP B: N-[2-phenyl-1-(2-thienyl)-ethenyl]-2,2,2-trifluoroimidoylchloride

Using the procedure of Step B of Example 4, 11.2 g of the product ofStep A were reacted to obtain 11.8 g of the expected product melting atless than 50° C.

STEP C: Diethyl1-[[1,2-bis-(4-chlorophenyl)-ethenyl]-imino]-2,2,2-trifluoromethyl]-propanedioate

Using the procedure of Step C of Example 4, 11.8 g of the product ofStep B and 12.5 ml of diethyl malonate were reacted to obtain 25.4 g ofthe expected product melting at 136° C.

STEP D: Ethyl4-hydroxy-5-phenyl-6-(2-thienyl)-2-(trifluoromethyl)-3-pyridinecarboxylate

Using the procedure of Step D of Example 4, 25.4 g of the product ofStep C were reacted to obtain 12 g of the expected product melting at136° C.

STEP E:4-hydroxy-5-phenyl-N-(2-thiazolyl)-6-(2-thienyl)-2-trifluoromethyl-3-pyridinecarboxamide

Using the procedure of Example 5, 10 g of amino thiazol and 6.9 g of theproduct of Step D were reacted to obtain 5.8 g of the expected productwhich was crystallized from acetonitrile melting at 260°-262° C.

Analysis: C₂₀ H₁₂ N₃ O₂ F₃ S₂ ; molecular weight=447.466. Calculated: %C 53.68, % H 2.70, % N 9.39, % F 12.74, % S 14.33. Found: % C 53.6, % H2.6, % N 9.4, % F 12.7 14.0.

EXAMPLE 104-hydroxy-6-methyl-5-phenyl-N-(2-thiazolyl)-2-trifluoromethyl-3-pyridinecarboxamide STEP A: Ethylα-[1-[(trifluoroacetyl)-amino]-ethylidene]-benzene acetate

A mixture of 18.8 g of powdered zinc and 400 ml of tetrahydrofuran wasrefluxed and 4 ml of ethyl α-bromophenyl acetate were added rapidly. Thereaction was initiated and then, away from reflux, 10.4 ml ofacetonitrile were added. Reflux was maintained by the slow addition of42.4 ml of ethyl α-bromophenyl acetate, and when the addition wasfinished, reflux was maintained for a further thirty minutes. Themixture was then poured at ambient temperature into a solution of 100 gof ammonium chloride in 750 ml of water, and the mixture was extractedwith ether. The extracts were washed with water, dried and concentratedto dryness under reduced pressure to obtain 50 g of an oil to which 120ml of pyridine were added. The mixture was stirred at +10° to +15° C.,and 31.14 ml of trifluoroacetic anhydride were added slowly. The mixturewas poured into 500 g of ice and 150 ml of concentrated hydrochloricacid, then was extracted with ether. The extracts were washed withwater, dried and concentrated to dryness under reduced pressure toobtain 62 g of an oil which was purified by chromatography on silica(methylene chloride - hexane 3-7) to obtain 35.5 g of the expectedproduct.

STEP B: -[1-[(trifluoroacetyl)-amino]-ethylidene]-benzene acetic acid

16.5 g of the product of Step A were dissolved in 15.6 ml oftrimethylsilane iodide and after 16 hours of reflux, the solution waspoured into 200 ml of a solution of sodium bisulfite and then wasextracted with ether. The extracts were washed with water, dried andconcentrated to dryness under reduced pressure to obtain 11.7 g of theexpected product which after crystallization from heptane melted at 174°C.

STEP C: N-(1-methyl-2-phenylethenyl)-2,2,2-trifluoroacetamide

To 11.7 g of the product of Step B, 60 ml of quinoline and 600 mg ofcopper chromite were added and the mixture with vigorous stirring wasplunged into a metallic bath heated to 230° to 240° C. for 10 minutes.The mixture was cooled and filtered, and the filtrate was taken up inether, washed with normal hydrochloric acid and then with water, driedand concentrated under reduced pressure to obtain 9.8 g of the expectedproduct.

STEP D: N-(1-methyl-2-phenylethenyl)-2,2,2-trifluoroethanimidoylchloride

Using the procedure of Step B of Example 4, 9.8 g of the product of StepC were reacted to obtain 10.5 g of the expected product.

STEP E: Ethyl[1-[(1-methyl-2-phenylethenyl)-2,2,2-trifluoroethanimidoyl]-propanedioate

Using the procedure of Step C of Example 4, 10.5 g of the product ofStep D were reacted to obtain 25 g of the expected product.

STEP F: Ethyl4-hydroxy-6-methyl-5-phenyl-2-(trifluoromethyl)-3-pyridine-carboxylate

Using the procedure of Step D of Example 4, 25 g of the product of StepE were reacted to obtain 5 g of the expected product melting at 82° to84° C.

STEP G:4-hydroxy-6-methyl-5-phenyl-N-(2-thiazolyl)-2-trifluoromethyl-3-pyridine-carboxamide

Using the procedure of Example 5, 6.25 g of 2-aminothiazole and 4 g ofthe product of Step F were reacted to obtain 3.7 g of the expectedproduct melting greater than 260° C. after crystallizing fromacetonitrile.

Analysis: C₁₇ H₁₂ N₃ O₂ F₃ S. Calculated: % C 53.82, % H 3.19, % N11.08, % F 15.02, % S 8.45. Found: % C 53.7, % H 3.1, % N 11.0, % F14.7, % S 8.5.

EXAMPLE 11 5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-3-pyridine carboxamideSTEP A: Ethyl 5,6-diphenyl-4-hydroxy-3-pyridine-carboxylate

15 g of 1,2-bis-phenylethanone were heated to reflux in 200 ml of xylenewith 1.5 g of p-toluene sulfonic acid and 18 g of diethyl aminomethylenepropanedioate were added in two lots. Reflux was maintained for 20minutes, followed by cooling, pouring into water, and extracting withethyl acetate. The extracts were dried and concentrated under reducedpressure to obtain 30 g of crude product which was chromatographed onsilica (eluent : ethyl acetate - n-hexane, 8-2) to obtain 1.8 g of theexpected product melting at 220° C.

STEP B: 5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-3-pyridine carboxamide

Using the procedure of Example 5, 2.5 g of 2-aminothiazole and 1.6 g ofthe product of Step A were reacted to obtain 1.2 g of the expectedproduct melting greater than 260° C. after crystallizing fromacetonitrile.

Analysis: C₂₁ H₁₅ N₃ O₂ S; molecular weight=373.437. Calculated: % C67.54, % H 4.05, % N 11.25, % S 8.59. Found: % C 67.4, % H 3.9, % N11.2, % S 8.5.

EXAMPLE 125,6-diphenyl-4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-3-pyridinecarboxamide STEP A: 1-amino-1,2-(diphenyl)-ethenyl

Using the procedure of Step A of Example 4, 39.2 g of1,2-diphenylethanone were reacted to obtain 39 g of the expectedproduct.

STEP B: N-(1,2-diphenylethenyl)-2-methoxy butanamide

To a stirred mixture of 39 g of the product of Step A, 300 ml oftetrahydrofuran and 20 ml of pyridine at 20° C., a solution of 27.3 mlof 2-methoxy butanic acid chloride in 100 ml of tetrahydrofuran wasadded. After refluxing for 1 hour, the mixture was poured into 300 ml ofa mixture of iced water and 2N hydrochloric acid, and was extracted withether. The extracts were washed with water and concentrated underreduced pressure to obtain 54 g of oil which was chromatographed onsilica (eluent : methylene chloride) to obtain 21 g of the expectedproduct melting at 78° to 80° C.

STEP C: N-(1,2-diphenylethenyl)-2-methoxy butanimidoyl chloride

A solution of 21 g of the product of Step B, 300 ml of methylenechloride and 49.5 ml of triethylamine was cooled to -40° C. and at -40°C. a solution of 9.42 g of diphosgene in 90 ml of methylene chloride wasadded. The residue, after returning the temperature to 20° C. andconcentrating the mixture under reduced pressure, was taken up in etherand filtered. The filtrate was concentrated under reduced pressure toobtain 23 g of the expected product.

STEP D: Ethyl[1-(1,2-diphenylethynylimino)-2-methoxybutyl]-propanedioate

Using the procedure of Step C of Example 4, 23 g of the product of StepC, 27 ml of ethyl malonate and 8.2 g of sodium hydride were reacted toobtain 54 g of the expected product.

STEP E: Ethyl 5,6-diphenyl-4-hydroxy-2-(1-methoxypropyl)-3-pyridinecarboxylate

Using the procedure of Step D of Example 4, 54 g of the product of StepD were reacted to obtain 8.2 g of the expected product which aftercrystallization from ether melted at 210° C.

STEP F:5,6-diphenyl-4-hyroxy-2-(1-methoxypropyl)-N-(2-thiazolyl)-3-pyridinecarboxamide

Using the procedure of Example 5, 9.3 g of the product of Step E and 12g of 2-aminothiazole were reacted to obtain 8.65 g of the expectedproduct which after crystallization from ether melted at 236° to 238° C.

STEP G:5,6-diphenyl-4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-3-pyridine-carboxamide

A solution of 8.65 g of the product of Step F and 86 ml of methylenechloride was cooled to -70° C. to -60° C. and while maintaining thistemperature, 116 ml of a solution of boron tribromide were added. Afterstirring for 24 hours, the temperature was allowed to return to ambient.The solution was poured into 180 ml of iced water and extracted withmethylene chloride. The extracts were washed with water, dried andconcentrated under reduced pressure. After chromatography under pressure(methylene-chloride - ethyl acetate 8-2), 4 g of the expected productwere obtained which after crystallization from ethyl acetate melted at232° to 234° C.

Analysis: C₂₄ H₂₁ O₃ N₃ S; molecular weight=431.517. Calculated: % C66.8 % H 4.9 % N 9.74. Found (not dried): % C 66.7 % H 4.8 % N 9.5.

Example of pharmaceutical compositions

Tablets were prepared containing 50 mg of the product of Example 3 andsufficient excipient of lactose, talc, starch and magnesium stearate fora final tablet of 350 mg.

PHARMACOLOGICAL STUDY Anti-Inflammatory Activity: Chronic-Arthritis withAdjuvant (Preventative Treatment)

In the rat, the injection of Freund type adjuvant in a rear paw causesthe rapid appearance of a primary inflammatory lesion in this paw andthen, after a latency period of 13 to 15 days, the start up of asecondary arthritic affection, particularly in the other rear paw. Thetest was carried out on male rats aged 42 to 50 days which received anintra-plantar injection of 0.1 ml of "Freund" type adjuvant (suspensionin vaseline oil of 6 mg per ml of killed mycobacterium butyricum). Theanimals received the product orally from day 0 (day of injection ofadjuvant) up to the day before they were killed, which occured on day17. Control arthritic animals and control normal animals received onlythe vehicle. The criteria of appreciation of the activity of thesubstances studied was the increases in volume of the injected rear paws(primary and secondary inflammation) and the non-injected ones(secondary inflammation) by comparison with the average volume of thecorresponding paws of normal controls. The DA₅₀ was determined, that isto say, the dose which reduced by 50% the increase in volume of the rearpaws of the treated animals in comparison with the control animals. Theresults obtained were as follows:

    ______________________________________                                        Product of Example                                                                            DA.sub.50 in mg/k                                             ______________________________________                                        1               0.3                                                           3               15                                                            ______________________________________                                    

Various modifications of the products and method of the invention may bemade without departing from the spirit or scope thereof and it is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

What we claim is:
 1. A pyridine compound of the formula ##STR19##wherein R is selected from the group consisting of thiazolyl or4,5-dihydrothiazolyl, substituted with alkyl of 1 to 5 carbon atoms, R₁and R₂ are individually selected from the group consisting of (a) alkylof 1 to 5 carbon atoms and (b) phenyl and naphthyl unsubstituted orsubstituted with a member of the group consisting of hydroxy, alkyl andalkoxy of 1 to 5 carbon atoms, halogen, --NO₃ and --CF₃, R₃ is selectedfrom the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms,--(CF₂)_(n) --CF₃ and ##STR20## n is an integer from 0 to 4 and Alk isalkyl of 1 to 5 carbon atoms or their non-toxic, pharmaceuticallyacceptable salts thereof.
 2. A compound of claim 1 wherein R is --CF₃.3. A compound of claim 1 wherein R₃ is --CF₃ or ##STR21## and Alk isalkyl of 1 to 5 carbon atoms.
 4. A compound of claim 1 wherein one of R₁and R₂ is methyl and the other is phenyl unsubstituted or substitutedwith a member of the group consisting of methyl, ethyl, methoxy, ethoxy,halogen and --CF₃ or R₁ and R₂ are both phenyl unsubstituted orsubstituted with a member of the group consisting of methyl, ethyl,methoxy, ethoxy, halogen and --CF₃.
 5. A compound of claim 1 selectedfrom the group consistingof:4-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-bis-(4-chlorophenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-diphenyl-4-hydroxy-2-(1-hyroxypropyl)-4-(2-thiazolyl)-3-pyridinecarboxamide,or their non-toxic, pharmaceutically acceptable salts withacids or bases.
 6. An anti-inflammatory or anti-rheumatic compositioncomprising an anti-inflammatory or anti-rheumatically effective amountof a compound of claim 1 and an inert pharmaceutical carrier.
 7. Acomposition of claim 6 wherein in the compound R₃ is --CF₃ or ##STR22##and Alk is alkyl of 1 to 5 carbon atoms.
 8. A composition of claim 6wherein in the compound one of R₁ and R₂ is methyl and the other isphenyl unsubstituted or substituted with a member of the groupconsisting of methyl, ethyl, methoxy, ethoxy halogen and --CF₃ or R₁ andR₂ are both phenyl unsubstituted or substituted with a member of thegroup consisting of methyl, ethyl, methoxy, ethoxy, halogen and --CF₃.9. A composition of claim 6 wherein the active compound is selected fromthe group consistingof:4-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-bis-(4-chlorophenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-diphenyl-4-hydroxy-2-(1-hydroxypropyl)-4-(2-thiazolyl)-3-pyridinecarboxamide,or their non-toxic, pharmaceutically acceptable additionsalts with acids or bases.
 10. A method of treating inflammation orrheumatism in warm-blooded animals which comprises administering towarm-blooded animals in need of said treatment an anti-inflammatory oranti-rheumatically effective amount of a compound of claim
 1. 11. Amethod of claim 10 wherein in the compound R₃ is --CF₃ or ##STR23## andAlk is alkyl of 1 to 5 carbon atoms.
 12. A method of claim 10 whereinone of R₁ and R₂ in said compound is methyl and the other is phenylunsubstituted or substituted with a member of the group consisting ofmethyl, ethyl, methoxy, ethoxy, halogen and --CF₃ or R₁ and R₂ are bothphenyl unsubstituted or substituted with a member of the groupconsisting of methyl, ethyl, methoxy, ethoxy, halogen and --CF₃.
 13. Amethod of claim 10 wherein the active compound is selected from thegroup consistingof:4-hydroxy-5-methyl-6-phenyl-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-diphenyl-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-bis-(4-chlorophenyl)-4-hydroxy-N-(2-thiazolyl)-2-(trifluoromethyl)-3-pyridinecarboxamide,5,6-diphenyl-4-hydroxy-2-(1-hydroxypropyl)-4-(2-thiazolyl)-3-pyridinecarboxamide,or their non-toxic, pharmaceutically acceptable additionsalts with acids and bases.